Potent antiretroviral therapy has had an impressive impact on mortality in HIV-infected subjects, but this success came at the expense of significant co-morbidities, including cardiovascular disease and diabetes. These co-morbidities have been linked to heightened inflammation and monocyte activation, but the etiology of this heightened activation/inflammation is not fully understood, but is partly due to gut epithelial barrier dysfunction and microbial translocation. Attempts at controlling inflammation, immune activation or microbial translocation in HIV+ treated subjects have been for the most part unsuccessful, and even treatment that have been successful (such as statins) have drug interactions and safety concerns, likely precluding their use in a large proportion of the HIV population. Safer strategies that could be more widely adopted are well needed. It has been estimated by the WHO that nearly two billion subjects may be zinc deficient in the developing countries. In the developed countries, prior to effective ART, zinc deficiency was prevalent in HIV-infected subjects, and had been independently linked to disease progression and to higher mortality. Unlike what is observed with most nutrients, the prevalence of zinc deficiency continues to be high, even in subjects on ART. For example, the Nutrition for Healthy Living study found that 38% of subjects on ART had zinc deficiency, and subjects in the upper quartiles of zinc levels had lower HIV-1 RNA levels than those in the lowest quartile. Thus far, there is a lack of data related to the contribution of zinc status to the heightened inflammation and monocyte activation in HIV. Also, the few available zinc-supplementation studies in HIV have been mostly in untreated or not optimally treated subjects, and no studies have assessed changes in inflammation markers after zinc supplementation in HIV+ subjects with virologic suppression on ART, a pertinent population to the current era of HIV infection where guidelines are calling for every HIV+ subject to be aggressively treated. In the R21 phase of the proposal, we will assess the prevalence of zinc deficiency in HIV-infected subjects on ART and compare it to that of a matched group of HIV negative controls. We will also study the relationships between zinc levels and systemic inflammation, innate immunity and gut epithelial barrier dysfunction. Lastly, we will conduct a pilot study testing two different doses of zinc supplementation in HIV-infected subjects on ART with documented zinc deficiency. This pilot trial will also explore whether this strategy may affect selected inflammation markers and will help guide the next phase of investigations. In the R33 phase, we will conduct a pilot randomized placebo-controlled study of zinc supplementation in HIV-infected subjects on ART with zinc deficiency, and we will assess whether zinc supplementation is safe and effective at increasing zinc levels, and whether it will affect different pathways involved in HIV-comorbidities, namely innate immunity, systemic inflammation, oxidative stress, and gut epithelial barrier dysfunction. Our proposal should provide important mechanistic insights to inform us on the mechanism of action through which zinc may produce clinical benefit in the HIV+ population, and as such will provide the information necessary to develop a competitive full-scale clinical trial.